Statin class drugs lower plasma cholesterol by repressing HMG-CoA Reductase, a key enzyme in the biosynthetic pathway of cholesterol. Statins have revolutionized cardiovascular treatment but a relatively large fraction of treated patients still go on to develop cardiovascular disease;therefore, alternative targets and approaches are needed. Recently small RNAs, and in particular miRNAs, have been shown to be key regulators of many genes. In order to examine a possible role of miRNAs in lipid metabolism, we examined the differential expression of miRNAs from the liver of mice fed a high fat diet for 3 weeks. In addition, the mRNA profile and proteome of the liver from chow fed versus high fat fed mice was examined. 5 miRNAs, which were up-regulated by more than 2-fold, were found to target several genes within the cholesterol biosynthetic pathway. Using reporter constructs containing the 3 untranslated region of the affected mRNAs, the target sites for the miRNAs were identified. Transfection of the identified miRNAs into hepatic cells was found to decrease acetate incorporation into cholesterol. This raises the possibility that small molecule drugs that act on the promoters of these miRNAs and or the miRNAs themselves could possibly be used to block cholesterol synthesis and reduce atherosclerosis in a mechanism similar to statins. Future studies will involve a detailed analysis of the promoter of these miRNAs and determining the spectrum of other genes that these miRNAs may target.